Influenza infection remains a major health concern causing morbidity and mortality, especially in elderly populations. Current vaccines rely on inducing neutralizing antibodies to coat proteins; however, these vaccines are ineffective against serologically distinct viral strains. Therefore, it is important to develop vaccines that induce cellular immunity as well. Although CD8 cytotoxic T cells have been shown to be important in controlling influenza viral infections, CD4 T cells also play an integral role in viral clearance and protection, especially in the absence of CD8 T cells. The mechanisms by which CD4 T cells promote viral clearance and protection remain poorly understood; however, IFN-gamma appears to be an important component of the CD4 response to influenza. For example, CD4 T cell effectors that produce IFN-gamma can protect against lethal influenza infection while cells deficient in this cytokine do not protect. During acute infection, the production of IFN-gamma appears linked to cell division with influenza specific CD4 cells in the airways expressing high amounts of this cytokine only after greater than six cell division. This proposal will examine the relationship between the ability of CD4 T cells to produce IFN-y and the ability to protect mice against lethal influenza infection. Aim 1 will use in vitro and in vivo protocols to generate CD4 effectors that are at distinct stages of differentiation based on IFN-gamma production. These effectors will then be analyzed for their ability to migrate to the lung and confer protection. Aim 2 will investigate the role of IFN-gamma in CD4 dependent survival during; influenza infection.